Deletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice.

The agouti-yellow (A(y)) deletion is the only genetic modifier known to suppress testicular germ cell tumor (TGCT) susceptibility in mice or humans. The A(y) mutation deletes Raly and Eif2s2, and induces the ectopic expression of agouti, all of which are potential TGCT-modifying mutations. Here we report that the reduced TGCT incidence of heterozygous A(y) males and the recessive embryonic lethality of A(y) are caused by the deletion of Eif2s2, the beta subunit of translation initiation factor eIF2. We found that the incidence of affected males was reduced 2-fold in mice that were partially deficient for Eif2s2 and that embryonic lethality occurred near the time of implantation in mice that were fully deficient for Eif2s2. In contrast, neither reduced expression of Raly in gene-trap mice nor ectopic expression of agouti in transgenic or viable-yellow (A(vy)) mutants affected TGCT incidence or embryonic viability. In addition, we provide evidence that partial deficiency of Eif2s2 attenuated germ cell proliferation and differentiation, both of which are important to TGCT formation. These results show that germ cell development and TGCT pathogenesis are sensitive to the availability of the eIF2 translation initiation complex and to changes in the rate of translation.

BAX-mediated cell death affects early germ cell loss and incidence of testicular teratomas in Dnd1(Ter/Ter) mice.

A homozygous nonsense mutation (Ter) in murine Dnd1 (Dnd1(Ter/Ter)) results in a significant early loss of primordial germ cells (PGCs) prior to colonization of the gonad in both sexes and all genetic backgrounds tested. The same mutation also leads to testicular teratomas only on the 129Sv/J background. Male mutants on other genetic backgrounds ultimately lose all PGCs with no incidence of teratoma formation. It is not clear how these PGCs are lost or what factors directly control the strain-specific phenotype variation. To determine the mechanism underlying early PGC loss we crossed Dnd1(Ter/Ter) embryos to a Bax-null background and found that germ cells were partially rescued. Surprisingly, on a mixed genetic background, rescued male germ cells also generated fully developed teratomas at a high rate. Double-mutant females on a mixed background did not develop teratomas, but were fertile and produced viable off-spring. However, when Dnd1(Ter/Ter) XX germ cells developed in a testicular environment they gave rise to the same neoplastic clusters as mutant XY germ cells in a testis. We conclude that BAX-mediated apoptosis plays a role in early germ cell loss and protects from testicular teratoma formation on a mixed genetic background.

Burned-out testicular germ cell tumour presenting as acute inferior vena cava syndrome.

Germ cell tumours (GCT) are the most common testicular neoplasms, seen mainly in young adults. Rarely they can affect extragonadal tissues, either as primary tumours or as metastases, most commonly to retroperitoneal lymph nodes. A 'burned-out' testicular tumour is a metastatic GCT with a relatively occult primary testicular tumour, which has histologically spontaneously regressed. We report a case of a 26-year-old man who presented with an acute history of lower back pain and leg swelling. CT demonstrated a large retroperitoneal soft tissue mass causing right-sided hydronephrosis with inferior vena cava and iliofemoral vein thrombosis. Although clinical examination of the testis was normal, ultrasound imaging of the scrotum identified a burned-out testicular primary. Orchiectomy confirmed the diagnosis and the patient responded well to chemotherapy, with no viable residual tumour on follow-up imaging. However, despite nephrostomy insertion, a dimercaptosuccinic acid (DMSA) scan demonstrated loss of function of the right kidney after treatment.

Functions of genes related to testicular germ cell tumour development.

OBJECTIVE: Testicular germ cell tumour (TGCT) is a malignancy with a high heritable component. The inherited risk is polygenic, and around 50 susceptibility genes are identified. The functional role of the gene products for TGCT development is not well understood. The focus of this review is functional studies of genetic risk factors for TGCT derived from GCNIS and the signalling pathways involved in the pathogenesis. RECENT DEVELOPMENTS: Genome-wide association studies have identified new risk loci for TGCT and confirmed previously identified susceptibility genes. Many of these risk genes are related to male germ cell development, sex determination and genomic integrity. Gain- and loss-of-function studies in animal models and TGCT cell lines, as well as gene and protein expression studies in TGCT patient samples, have contributed to the understanding of TGCT development. KITLG-KIT signalling is of crucial importance, but several other signal transduction pathways may also play a role. Many of the risk loci are in non-coding regions, and studies have revealed that non-coding RNAs may act as oncogenes or tumour suppressors in TGCT development. CONCLUSIONS: The risk of TGCT is polygenic, and the underlying molecular mechanisms are complex. Several signalling pathways are related to TGCT development, and both proteins and non-coding RNAs may act as oncogenes or tumour suppressors. Epigenetic studies are of importance to get further knowledge about how the signalling pathways are regulated.

Environment, testicular dysgenesis and carcinoma in situ testis.

The testicular dysgenesis syndrome (TDS) hypothesis proposes that a proportion of the male reproductive disorders-cryptorchidism, hypospadias, infertility and testicular cancer-may be symptoms of one underlying developmental disease, TDS, which is most likely a result of disturbed gonadal development in the embryo. TDS may be caused by genetic factors, environmental/life-style factors, or a combination of both. Some rare disorders of sex development of genetic origin are among the best-known examples of severe TDS. Among the environmental and life-style factors that are suspected to influence the hormonal milieu of the developing gonad are the endocrine disrupters. A prenatal exposure to commonly used chemicals, e.g. phthalates, may result in a TDS-like phenotype in rats. Currently, this animal model is the best model for TDS. In humans the situation is much more complex, and TDS exists in a wide range of phenotypes: from the mildest and most common form, in which impaired spermatogenesis is the only symptom, to the most severe cases, in which the patient may develop testicular cancer. It is of great importance that clinicians in different specialties treating patients with TDS are aware of the association between the different symptoms.

Development of teratomas from the ectoderm of mouse egg cylinders.

We studied the developmental capacities of the primary ectoderm and endoderm of 6-day embryos of hybrids between strains 129/Sv-SIJ C P and A/He mice by grafting these germ layers into the testes of adult mice for 30 days. Grafts of embryonic ectoderm gave rise to teratocarcinomas composed of undifferentiated embryonal cells and derivatives of all three germ layers including respiratory and alimentary epithelium. Grafts of extraembryonic ectoderm gave rise to invasive trophoblastic giant cells. Grafts of endoderm did not develop.

[Increased risk of testicular dysgenesis?]. / Økt forekomst av utviklingsfeil i testiklene?

The latest figures from the Cancer Registry of Norway show that Norway has the highest incidence rate of testicular cancer in the world. They also show that the incidence rate continues to increase, as it has for the last decades in the western world. The reasons for this increase, which might also be true for urogenital abnormalities in men and reduced sperm quality, are uncertain. Data suggest, however, that these anomalies originate in foetal life, and that contributing factors are genetic, pregnancy-related and environmental. The potential importance of environmental factors must be taken seriously, and the authorities must take action to strengthen the research in this area.

Primary retroperitoneal seminoma - embryology, histopathology and treatment particularities.

INTRODUCTION: Retroperitoneal seminoma is a very rare form of cancer, with embryological origin represented by primordial germ cells from the urogenital ridges left behind during the fetal development. Extragenital germ cell tumors can also occur in the mediastinum or the pineal gland. The aim of this paper is to outline the particularities and draw embryological, histopatological and treatment conclusions regarding extragonadal germ cell tumors. PATIENT AND METHODS: A 43-year-old patient without any additional pathology was admitted for anemia of unknown etiology. The clinical examination revealed through deep abdominal palpation a mass in the left flank, and normal testes. Thoraco-abdomino-pelvic computed tomography (CT) scan showed a large retroperitoneal tumor adjacent to the great vessels in the left lumbo-iliac region. The blood work revealed just a low hemoglobin and hematocrit. With the established diagnosis of retroperitoneal tumor, radical surgical removal was decided. During the surgery, we were required to dissect a large solid encapsulated tumor mass from the aorta and the common iliac artery, starting at the renal pedicle all the way to the left iliac bifurcation. The surgical access was obtained through a transperitoneal left subcostal incision prolonged pararectally. Histopathological and immunohistochemical studies revealed a seminoma of the usual type. After the histological findings, the patient's tumor markers were investigated (LDH - lactate dehydrogenase, ßHCG - beta-human chorionic gonadotropin, αFP - alpha-fetoprotein), all values being within normal ranges. In addition, the left testicle was thoroughly reexamined, clinically, through ultrasound and magnetic resonance imaging (MRI) scans, and no abnormalities were observed. After the surgery, the patient followed three courses of chemotherapy (BEP - Bleomycin, Etoposide and Cisplatin). RESULTS: The CT scan done 24 months after surgery found no signs of local or distant tumor recurrence. The patient entered a follow-up schedule consisting of periodical clinical, serological and imagistic evaluations. CONCLUSIONS: Primary retroperitoneal seminoma is a rare entity that must be taken into account when treating a retroperitoneal tumor. It develops out of the urogenital ridge, while the testes are normal. Thorough testicular evaluation (clinical, ultrasound and serum markers) is mandatory in all retroperitoneal tumors. The histopathological analysis is crucial for an accurate diagnosis and a proper management strategy. Through radical surgery and chemotherapy, the patients that are diagnosed prior to massive visceral metastatic dissemination can be cured.

Limb deficiency and splenogonadal fusion.

We report a 10-year-old boy with tetramelic limb deficiencies, splenogonadal fusion, and mild mandibular and oral abnormalities. This patient is quite typical of 14 reported cases with this combination of findings. This association must be nosologically closely related to the Hanhart syndrome and other syndromes of limb deficiency and orofacial abnormalities. Recent experience does not support the idea that limb reduction with splenogonadal fusion is an invariably lethal dominant disorder.

Fetal gonadoblastoid testicular dysplasia.

The case of a 950-g male infant born at 28 weeks of gestation with bilateral gonadoblastoma-like testicular lesions who lived for one hour is presented. The infant had a 46, XY karyotype and multiple congenital anomalies.

Role of gain of 12p in germ cell tumour development.

Within the human testis, three entities of germ cell tumours are distinguished: the teratomas and yolk sac tumors of newborn and infants, the seminomas and nonseminomas of adolescents and young adults, referred to as testicular germ cell tumours (TGCT), and the spermatocytic seminomas. Characteristic chromosomal anomalies have been reported for each group, supporting their distinct pathogenesis. TGCT are the most common cancer in young adult men. The initiating pathogenetic event of these tumours occurs during embryonal development, affecting a primordial germ cell or gonocyte. Despite this intra-uterine initiation, the tumour will only be clinically manifest after puberty, with carcinoma in situ (IS) as the precursor. All invasive TGCT, both seminomas and nonseminomas, as well as CIS cells are aneuploid. The only consistent (structural) chromosomal abnormalities in invasive TGCT are gains of the short arm of chromosome 12, mostly due to isochromosome (i(12p)) formation. This suggests that an increase in copy number of a gene(s) on 12p is associated with the development of a clinically manifest TGCT. Despite the numerous (positional) candidate gene approaches that have been undertaken thus far, identification of a causative gene(s) has been hampered by the fact that most 12p gains involve rather large genomic intervals, containing unmanageable numbers of candidate genes. Several years ago, we initiated a search for 12p candidate genes using TGCT with a restricted 12p-amplification, cytogenetically identified as 12p11.2-p12.1. This approach is mainly based on identification of candidate genes mapped within the shortest region of overlap of amplification (SROA). In this review, data will be presented, which support the model that gain of 12p-sequences is associated with suppression of apoptosis and Sertoli cell-independence of CIS cells. So far, DAD-R is one of the most likely candidate genes involved in this process, possibly via N-glycosylation. Preliminary results on high through-put DNA- and cDNA array analyses of 12p-sequences will be presented.

Intratesticular papillary mucinous cystadenocarcinoma.

The first case of intratesticular papillary mucinous cystadenocarcinoma is described. The tumor was histopathologically different from other types of papillary carcinoma related to the testicle and is believed to have originated from an intratesticular müllerian duct remnant.

Spectrum of germ cell tumors: from head to toe.

Germ cell tumors (GCTs) occur most frequently in the gonads and are relatively rare in other sites, such as the pineal gland, neurohypophysis, mediastinum, and retroperitoneum. GCTs are thought to originate from primordial germ cells, which migrate to the primitive gonadal glands in the urogenital ridge. Extragonadal GCTs might also originate from these cells when the cells are sequestered during their migration. Pathologic subtypes of GCTs vary, and the prevalence of mixed tumors is high. These factors produce a diversity of radiologic findings and make prospective radiologic diagnosis difficult in many cases. However, similar radiologic findings have been observed in pathologically equivalent tumors in varying sites. Seminomas appear as uniformly solid, lobulated masses with fibrovascular septa that enhance intensely. Nonseminomatous GCTs appear as heterogeneous masses with areas of necrosis, hemorrhage, or cystic degeneration. Fat and calcifications are hallmarks of teratomas, most of which are benign. In immature teratomas, scattered fat and calcification within larger solid components are occasionally seen. These imaging characteristics reflect the pathologic features of each tumor, and histologically similar GCTs at varying sites have similar radiologic features. Knowledge of the pathologic appearances of GCTs and their corresponding radiologic appearances will allow radiologists to diagnose these tumors correctly.

Case report: cystic fibrosis and embryonal carcinoma of the testis.

The authors describe a patient with cystic fibrosis and a stage III testicular embryonal cell cancer. Because cystic fibrosis occurs in approximately 1 of 2,500 births and embryonal carcinoma in 3 of 100,000, the likelihood of concurrence for both disorders in the same patient is approximately 1 in 80 million. Involvement of the vas deferens in cystic fibrosis raises the possibility of a fundamental embryologic basis that explains the pathogenesis of this association.

Embryology of the gonad with reference to special tumors of the ovary and testis.

The ovaries and testes have very similar development patterns until about the fourth month of embryonic life. A review of the similar development (until the fourth month) provides an explanation for the origin of tumors commonly associated with ovarian tissue appearing in the testis and vice versa. Embryonic surface epithelium gives rise to mesothelial tissue from which the common epithelial tumors arise in the ovary. Since these cells disappear from the testis when the tunica albuginea develops, this offers an explanation for the lack of common epithelial tumors in the testis. The embryonic gonadal tissue or sex cord epithelium and the primitive germ cells give rise to similar tumors in both the ovary and the testis. The extraembryonal tumors arise from the extraembryonal cells and trophoblastic cells, which give rise to the endodermal sinus tumors and choriocarcinomas, respectively. Since there is such a similarity in the development of the ovary and testis with the potential for residual cells to remain, an explanation is offered for the development of similar tumors in the ovary and the testis.

[Significance of the endodermal sinus tumor (Teilum) and of simplified teratoma of vitelline determination]. / Signification de la tumeur des sinus endodermiques (Teilum) et des tératomes simplifiés à détermination vitelline

The histogenesis of yolk-sac tumors has been explained by a selective cloning for extra-embryonic entoblast amongst totipotent carcinoma stemcells. The diverses appearances of the tumor growths are expressed mainly in the range of cyto-differentiations of entoblastic tissue rather than in their ability to form structures which mimick the yolk-sac. The process is clearly apparent in embryoids which are becoming disorganized and during the course of experimentally induced mouse parietal endodermal carcinoma. The latter's appearance is strong evidence that the laws of specificity are obeyed. Human tumors should be analyzed through human embryology. Some paradoxical aspects emerge occasionally due to the angiogenesic capabilities of the neoplastic vitelline tissue, and to the correlations of this tissue with the stromal vascular response.

[Experimental teratocarcinoma in mice: a model system for the study of the relationship between cellular surface antigens and embryonic differentiation]. / Le tératocarcinome expérimental de la souris: un système modèle pour l'étude des relations entre antigènes des surfaces cellulaires et différenciation embryonnaire

Several cell lines (either of embryonal carcinoma or of differentiated cells derived from teratomas) have been established in vitro from transplantable testicular teratomas. Primitive cell lines, propagated in vitro as embryonal carcinoma have retained the ability of the original tumor to differentiate in vivo or in vitro into must embryonic cell types. Features of this model system for study of early embryogenesis are described. Emphasis is placed on the description of the cell surface antigens of several cell lines. Syngeneic antisera raised against two primitive lines (F9 and PCC4) and against a differentiated one (Endo) have allowed the detection of three groups of cell surface antigens, present on teratoma cells, tumor cells and embryonic cells. The F9 antigen appears to be specific to be specific of the very early steps of egg development (morula and blastocyst). After egg implantation, it keeps expressed on the cells of the male germ line. The PCC4 antigen has a similar cell type distribution but appears to be more specific of multipotential cells. The Endo antigen is essentially specific of endodermal derivatives. The F9 antigen is probably specified by the wild type allele (+ tl2) of the tl2 gene at the T-Locus of the mouse, a gene which plays some critical role in early development. The molecular structure of this antigen, as determined from immunoprecipitates is very similar to that of H-2 antigens. In addition, a cross-reacting material is found in Man, with a tissue distribution identical to that found in the mouse.